While the incidence of HPV-related OPSCCs is increasing, these cancers usually have better prognoses and clinical outcomes than HPV-unrelated OPSCCs, which are typically related to smoking and alcohol use. This difference has been hypothesized to be due, at least in part, to the fact that inactivation of critical cancer pathways in HPV-related OPSCCs is caused by the presence of viral genes rather than somatic mutations or genetic/epigenetic inactivation of key tumor suppressor genes (as is the case for HPV-unrelated OPSCCs). This difference suggests that some of these pathways might be partially active or recoverable, leading to better responses to therapies that, for example, activate p53-mediated apoptosis. The exact mechanisms are still not fully known, but clinicians are nonetheless exploring less aggressive treatment options for HPV-related cancers as a way to minimize secondary effects and sequelae (treatment de-escalation). Here we propose to investigate the impact of treatment de-escalation and its possible non-inferiority in treatment trials and evaluate the impact of treatment de-escalation for HPV-related OPSCCs using data from treatment trials and natural history models of cancer recurrence.